Showing papers by "Massimo Tommasino published in 1999"
TL;DR: Swedish and Italian women with HPV 16-positive cervical disease were checked for codon 72 polymorphisms of p53 and arginine homozygotes were enriched in cancer compared with controls and precursor lesions.
133 citations
TL;DR: C/EBPalpha-mediated proliferation arrest and differentiation pathways can be separated by the E7 oncoprotein of the "high-risk" human papilloma virus without compromising the transactivation activity of C/ EBPalpha or its ability to participate in differentiation.
Abstract: Cell proliferation and terminal differentiation are mutually exclusive in most cell lineages. The b-zip transcription factor CCAAT/enhancer-binding protein α (C/EBPα) induces proliferation arrest and differentiation in many cell types, suggesting that both activities are linked. Here we show that C/EBPα-mediated proliferation arrest and differentiation pathways can be separated by the E7 oncoprotein of the “high-risk” human papilloma virus 16. The E7 oncoprotein overrides C/EBPα-mediated cell cycle withdrawal without compromising the transactivation activity of C/EBPα or its ability to participate in differentiation. Uncoupling of both pathways depends on the casein kinase II site of the oncoprotein but not on its ability to neutralize pocket proteins or the cyclin-dependent kinase inhibitor protein p21. Our results suggest a bifurcation of C/EBPα-mediated proliferation arrest and differentiation pathways.
60 citations
TL;DR: It is concluded that the CKI neutralization by HPVs is likely to be required for viral DNA replication rather than for malignant transformation of the host cell.
Abstract: High risk types of human papillomavirus (HPV) are agents in the aetiology of cervical carcinoma. The products of two early genes, E6 and E7, appear to be the principal transforming proteins. Studies of various monolayer cell culture systems have shown that the E7 oncoprotein of human papillomavirus type 16 is able to neutralize or bypass the inhibitory effect of the cell cycle-dependent kinase (CDK) inhibitors (CKIs) p21WAF1/CIP1 and p27KIP1. To understand whether the p21WAF1/CIP1 or p27KIP1 neutralization also plays a role in vivo, we performed studies on clinical specimens. Forty-five cervical biopsies, including HPV-negative mucosa, HPV 16-positive preinvasive (low and high grade lesions) and invasive neoplasia as well as HPV 6-positive condyloma acuminatum were analysed by single and double immunohistology. We examined the positive cell cycle regulator cyclin A and the universal cell cycle marker Ki67 as well as the negative cell cycle regulators p21WAF1/CIP1 and p27KIP1. Here, we show that in a significant fraction of cells the G1 block can be overcome despite high levels of CKIs in HPV lesions. This phenomenon, which was more evident for p21WAF1/CIP1 than for p27KIP1 was most marked in low grade lesions and in condylomata acuminata, in which a high viral productivity is expected. These results indicate that the overriding of CKI inactivation by viral oncoproteins appears to be a conserved property between low and high risk HPV types. We conclude that the CKI neutralization by HPVs is likely to be required for viral DNA replication rather than for malignant transformation of the host cell.
46 citations